TAR DNA-binding protein 43 (TDP-43) has been shown to bind both DNA and RNA and have multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation. It belongs to the hnRNP protein family and is highly expressed in the pancreas, placenta, lung, genital tract and spleen[1]. Characterisation of transcriptome-wide binding sites revealed that thousands of RNAs are bound by TDP-43 in neurons. TDP-43 regulates alternate splicing of the CFTR gene. The resulting aberrant splicing is associated with pathological features typical of cystic fibrosis.
TDP-43 is predominantly located in the nucleus under normal physiological conditions. However, hyperphosphorylated, fragmented and ubiquitinated forms of TDP-43 have been identified as core components of cytosolic inclusions in sporadic ALS and frontotemporal lobar degeneration (FTLD) [2,3,4,5,6,7,8]
TDP-43 contains a nuclear localising signal (NLS) as well as a nuclear export signal (NES)[8], which enables the shuttling of TDP-43 between the nucleus and the cytosol. Under normal conditions, TDP-43 interacts with mRNAs on which ribosomes are located separately, forming polysomes. Various stresses can induce clustering of ribosomes into a stalled state, resulting in the formation of stress granules (SG) containing TIA-1, G3BP, ataxin-2 and eIF4G1/2.
In the stalled state, transcription is inhibited as a homeostatic response. However, sustained stress and ensuing TDP-43 misfolding creates aberrant SGs and pathogenic TDP-43 aggregates [9]. Moreover, membrane-less organelles in the cytosol formed by the liquid?liquid phase separation of RNPs4 and RNA13 are implicated in TDP-43 proteinopathy. Misfolding and cytosolic mislocalisation also lead directly to a loss of normal TDP-43 function, and the resultant disruption of protein and RNA homeostasis is considered another likely pathogenic mechanism14 in addition to the toxicity of inclusions [9].
Mutations in TDP-43 have been associated with amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease and Alzheimer's disease.
Product Type:
NS Reagents Antibody
Antibody Type:
Monoclonal
Format:
100 µg in 100 µl PBS containing 0.02% sodium azide.
1. Strong MJ, Volkening K, Hammond R, et al. (2007). TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Molecular and Cellular Neuroscience. 35 (2): 3207.
2. Kwong LK, Neumann M, Sampathu DM, et al. (2007). TDP-43 proteinopathy: The neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease. Acta Neuropathologica. 114 (1): 6370.
3. Arai, T. et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602611 (2006). CAS
4. Neumann M, Sampathu DM, Kwong LK, Truax AC, et al. (2006). Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. Science. 314 (5796): 1303.
5. Tan, C. F. et al. TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol. 113, 535542 (2007).
6. Igaz, L. M. et al. Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am. J. Pathol. 173, 182194 (2008).
7. Tremblay C, St-Amour I, Schneider J, et al. (2011). Accumulation of transactive response DNA binding protein 43 in mild cognitive impairment and Alzheimer disease. J Neuropathol Exp Neurol. 70 (9): 78898.
8. Winton, M. J. et al. Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation. J. Biol. Chem. 283, 1330213309 (2008).
9. Yoshitaka Tamaki et al. Elimination of TDP-43 inclusions linked to amyotrophic lateral sclerosis by a misfolding-specific intrabody with dual proteolytic signals. Scientific Reports: volume 8, Article number: 6030 (2018)
TAR DNA-binding protein 43 (TDP-43) has been shown to bind both DNA and RNA and have multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation. It belongs to the hnRNP protein family and is highly expressed in the pancreas, placenta, lung, genital tract and spleen[1]. Characterisation of transcriptome-wide binding sites revealed that thousands of RNAs are bound by TDP-43 in neurons. TDP-43 regulates alternate splicing of the CFTR gene. The resulting aberrant splicing is associated with pathological features typical of cystic fibrosis.
TDP-43 is predominantly located in the nucleus under normal physiological conditions. However, hyperphosphorylated, fragmented and ubiquitinated forms of TDP-43 have been identified as core components of cytosolic inclusions in sporadic ALS and frontotemporal lobar degeneration (FTLD) [2,3,4,5,6,7,8]. TDP-43 contains a nuclear localising signal (NLS) as well as a nuclear export signal (NES)[8], which enables the shuttling of TDP-43 between the nucleus and the cytosol. Under normal conditions, TDP-43 interacts with mRNAs on which ribosomes are located separately, forming polysomes. Various stresses can induce clustering of ribosomes into a stalled state, resulting in the formation of stress granules (SG) containing TIA-1, G3BP, ataxin-2 and eIF4G1/2.
In the stalled state, transcription is inhibited as a homeostatic response. However, sustained stress and ensuing TDP-43 misfolding creates aberrant SGs and pathogenic TDP-43 aggregates [9]. Moreover, membrane-less organelles in the cytosol formed by the liquid?liquid phase separation of RNPs4 and RNA13 are implicated in TDP-43 proteinopathy. Misfolding and cytosolic mislocalisation also lead directly to a loss of normal TDP-43 function, and the resultant disruption of protein and RNA homeostasis is considered another likely pathogenic mechanism14 in addition to the toxicity of inclusions [9].
Mutations in TDP-43 have been associated with amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease and Alzheimer's disease.
Product Type:
NS Reagents Antibody
Antibody Type:
Monoclonal
Format:
100 µg in 100 µl PBS containing 0.02% sodium azide.
1. Strong MJ, Volkening K, Hammond R, et al. (2007). TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Molecular and Cellular Neuroscience. 35 (2): 3207.
2. Kwong LK, Neumann M, Sampathu DM, et al. (2007). TDP-43 proteinopathy: The neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease. Acta Neuropathologica. 114 (1): 6370.
3. Arai, T. et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602611 (2006). CAS
4. Neumann M, Sampathu DM, Kwong LK, Truax AC, et al. (2006). Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. Science. 314 (5796): 1303.
5. Tan, C. F. et al. TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol. 113, 535542 (2007).
6. Igaz, L. M. et al. Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am. J. Pathol. 173, 182194 (2008).
7. Tremblay C, St-Amour I, Schneider J, et al. (2011). Accumulation of transactive response DNA binding protein 43 in mild cognitive impairment and Alzheimer disease. J Neuropathol Exp Neurol. 70 (9): 78898.
8. Winton, M. J. et al. Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation. J. Biol. Chem. 283, 1330213309 (2008).
9. Yoshitaka Tamaki et al. Elimination of TDP-43 inclusions linked to amyotrophic lateral sclerosis by a misfolding-specific intrabody with dual proteolytic signals. Scientific Reports: volume 8, Article number: 6030 (2018)
Uniprot ID:
Q13148
Gene ID:
23435
Release Date:
Oct-17
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